Neural activity creates a spatio-temporally localized increase in blood supply known as functional hyperemia, known to underlie neuroimaging signals such as functional magnetic resonance imaging. The 'Hemo-Neural hypothesis,'recently proposed by sponsor Dr. Christopher Moore, predicts that hyperemia may also modulate neural excitability. Hemo-Neural influence may be mediated indirectly via glial cells or directly by temperature change, blood borne diffusible messengers such as nitric oxide, or activation of force-gated ion channels in neural membranes. I will test the specific hypotheses that hyperemia enhances the sensory response of pyramidal neurons, and diminishes the response of fast-spiking interneurons in mouse barrel cortex. I will test these predictions using a two-fold approach that combines physiological experimental techniques of tetrode recording and two-photon imaging with biophysically realistic computational modeling. These techniques will be used to test the activation of fast spiking interneurons and pyramidal cells in baseline and pharmacalogically induced hyperemia. Use of mice will allow me to identify genetically labeled specific cell-types in the 2-photon portion of my research. My results will direct the development of a computational model of a cortical neural and vascular network, from which we will investigate how hemo-induced effects may modulate neural activity. From the model, we will develop quantitative predictions of the direct effects of hyperemia on network activity that will guide future experiments. Abnormal interactions between the vascular and neural systems are associated with many neurological illnesses, including Alzhelmers, migraine, stroke and epilepsy, though these interactions have not been a subject of therapeutic development. Thus, the experimental and computational work proposed here may lay the groundwork for study of a new class of possible therapeutic targets in these conditions. PHS 416-1 (Rev. 9/08) Page 2 Number pages consecutively at the bottom throughout Form Page 2 the application. Do not use suffixes such as 2a, 2b. Kirschstein-NRSA Individual Fellowship Application NAME OF APPLICANT (Last, first, middle initial) Vierling-Claassen, Dorea L (To be completed by applicant- follow PHS 416-1 Instructions) 18.